The serotonergic neural system of the brain has been shown to influence a variety of physiologic functions which manifest themselves in a variety of disorders such as Alzheimer's disease, cognition disorders, irritable bowel syndrome, nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhythmia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.
Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries. This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type II diabetes. One area of obesity research has been investigating the activation of serotonergic systems, either by direct activation of serotonin receptor subtypes or by inhibiting serotonin reuptake.
Multiple serotonin (5-hydroxytryptamine or 5-HT) serotonin receptor subtypes have been identified and cloned. One of these, the 5-HT6 receptor, has been cloned by several groups (see, e.g., Ruat, M. et al. (1993) Biochem. Biophys. Res. Commun. 193: 268-276; Sebben, M. et al. (1994) NeuroReport 5: 2553-2557). The 5-HT6 receptor (5-HT6R) is positively coupled to adenylyl cyclase and regulates several neurotransmitter systems including glutamate, aspartate and acetylcholine. 5-HT6Rs have been mainly localized in olfactory tubercles, striatum, nucleus accumbens, and hippocampus with lower levels also found in amygdala and hypothalamus. Recent reports demonstrated a hypophagic effect for 5-HT6 antagonists in rats that was associated with an enhancement of the satiety sequence. The effect of 5-HT6 antagonists and 5-HT6 antisense oligonucleotides to reduce food intake in rats has been reported (Bentley, J. C. et al. (1999) Br J Pharmac. Suppl. 126. P66; Bentley, J. C. et al. (1997) J. Psychopharmacol. Suppl. A64, 2155). Compounds with enhanced affinity and selectivity for the 5-HT6 receptor have been identified in a number of studies, e.g., by Isaac, M. et al. (2000) Bioorganic & Medicinal Chemistry Letters 10: 1719-1721); and in patent publications such as WO 00/34242, WO99/37623, WO 99/42465, and WO 99/02502. 5-HT6 mRNA appears to be almost exclusively present in the brain with little evidence for its presence in peripheral tissues. Therefore, 5-HT6 antagonism has been proposed as a promising approach for treating cognitive impairment associated with neuropsychiatric disorders (e.g., Alzheimer.s disease, schizophrenia) without having potential peripheral side effects.
5-HT6R is associated with schizophrenia, bipolar affective disorders, Parkinson's and Alzheimer's disease. Furthermore, this receptor displays affinity for antidepressants such as clozapine. 5-HT is thought to be involved in schizophrenia because hallucinogens are induced by LSD, a known 5-HT2A agonist. Clozapine blocks the 5-HT2 subtype of serotonin receptor. It has been found that in schizophrenia, there is a reduced number of 5-HT2A receptors and an increase in the number of 5-HT1A receptors in the frontal cortex.
The dopamine D3 receptor is abundant in the mesolimbic and mesocortical dopamine terminal areas that are known to play a role in learning and memory. Polymorphism of the receptor has been associated with a small increase in vulnerability to schizophrenia. Moreover, there is increasingly strong evidence that D3 receptor antagonists will be effective antipsychotic agents, mainly by ameliorating the negative and cognitive symptoms of schizophrenia. Selective D3 receptor antagonists, such as nafadotride, reverse a scopolamine-induced deficit in both the passive avoidance paradigm and a spatial learning task in a water maze labyrinth in the rat, without having any detrimental effect on memory in non-impaired rats. The dopamine D3 receptor is therefore also considered to a potential therapeutic target for improving the cognitive impairments frequently seen in schizophrenia. The effect of combined blockade of 5-HT6 and dopamine D3 receptors has not been evaluated yet because of the lack of selective HT6/D3 antagonists.
“Typical” antipsychotics (sometimes referred to as conventional antipsychotics or conventional neuroleptics) include molindone, perphenazine, pimozide, thioridazine, thiothixene, trifluoperazine, chlorpromazine, fluphenazine, haloperidol, loxapine, and mesoridazine. Disadvantages with typical antipsychotics are well-known, e.g., 30-40% of patients do not respond during an acute schizophrenic episode; they are largely ineffective against the negative symptoms of schizophrenia; they are associated with medication compliance problems; up to 40% of patients will relapse within two years despite prophylaxis; and up to 75% of patients will experience extrapyramidal side-effects (EPSE);
5% of patients per year will develop tardive dyskinesia. Typical antipsychotics are generally being replaced by atypical antipsychotics (also known as second generation antipsychotics.)) The Atypical drugs include: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. These drugs are generally better tolerated than conventional drug therapy; have a lower observed rate of EPSE; are at least as clinically effective as conventional drug therapy; and have the potential to influence negative symptoms. Also, some studies indicate a modest improvement in cognition. But while the atypical drugs are an improvement over conventional antispsychotics, they are not without side effects, which include: drowsiness and weight gain; possible increase in the risk of type II diabetes and high levels of triglycerides in the blood; muscle tremor, uncontrolled movements of the face and arms (tardive dyskinesia), and muscle damage. Newer antipsychotics are less likely to cause tremor, muscle stiffness, uncontrolled movements, and fever and muscle damage. Clozapine (CLOZARIL) can cause bone marrow suppression, reduced white blood cell count, and seizures, though it is often effective in people who are not responsive to other drugs. Clozapine and Olanzapine (ZYPREXA) are most likely to cause weight gain; Ziprasidone (GEODON) does not appear to cause weight gain, but may lead to abnormalities on electrocardiogram.
Cognitive impairment is a debilitating feature of schizophrenia. 5-HT6 antagonists have positive effects on cognition; where a current therapies for schizophrenia (see the drugs noted above) have variable effects on cognition. 30-70% of patients receiving second-generation drugs have improvement on neuropsychological tests of cognition (particularly attention and short-term memory); improvement in these functions is seen in only 30% of patients receiving first-generation drugs. It has also been noted that 5-HT6 mRNA is decreased in hippocampus of post-mortem schizophrenia patients; atypical anti-psychotics (e.g., olanzapine) have high affinity for 5-HT6; 5-HT6 is highly expressed in dopamine-rich areas (striatum, nucleus accumbens); and 5-HT6 is localized on striatal gamma-amino butyric acid (GABA)-ergic interneurons, which also receive dopaminergic input.
Targeting 5-HT6R is further believed to attenuate dopamine activity (striatal) responsible for the extrapyramidal side effects of older anti-psychotics; a positive genetic association was found between the C267T polymorphism in 5-HT6 and the effectiveness of clozapine in patients refractory to treatment. Thus, high affinity compounds to 5-HT6R represent a real potential for treating cognitive dysfunction, e.g., in schizophrenia. A 5-HT6 receptor antagonist may be used as an add-on or combination therapy with other atypical drugs (e.g., clozapine) to treat the positive, negative and cognitive symptoms of schizophrenia with no side effect such as weight gain.